A phase I study of talazoparib (BMN 673) combined with carboplatin and paclitaxel in patients with advanced solid tumors (NCI9782).

Autor: Leal TA; Winship Cancer Institute, Emory University, Georgia., Sharifi MN; University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA., Chan N; Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA., Wesolowski R; Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA., Turk AA; Indiana University Simon Comprehensive Cancer Center, Indianapolis, Indiana, USA., Bruce JY; University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA., O'Regan RM; Department of Medicine, University of Rochester, Rochester, New York, USA., Eickhoff J; Department of Biostatistics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA., Barroilhet LM; Department of Obstetrics and Gynecology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA., Malhotra J; Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA., Mehnert J; Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, New York City, USA., Girda E; Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA., Wiley E; Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA., Schmitz N; School of Pharmacy, University of Wisconsin, Madison, Wisconsin, USA., Andrews S; University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA., Liu G; University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA., Wisinski KB; University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA.
Jazyk: angličtina
Zdroj: Cancer medicine [Cancer Med] 2022 Nov; Vol. 11 (21), pp. 3969-3981. Date of Electronic Publication: 2022 Apr 08.
DOI: 10.1002/cam4.4724
Abstrakt: Background: Inhibitors of poly(ADP-ribose) polymerase (PARP) proteins potentiate antitumor activity of platinum chemotherapy. This study sought to determine the safety and tolerability of PARP inhibitor talazoparib with carboplatin and paclitaxel.
Methods: We conducted a phase I study of talazoparib with carboplatin AUC5-6 and paclitaxel 80 mg/m 2  days 1, 8, 15 of 21-day cycles in patients with advanced solid tumors. Patients enrolled using a 3 + 3 design in two cohorts with talazoparib for 7 (schedule A) or 3 days (schedule B). After induction with 4-6 cycles of triplet therapy, patients received one of three maintenance options: (a) continuation of triplet (b) carboplatin/talazoparib, or (c) talazoparib monotherapy.
Results: Forty-three patients were treated. The MTD for both schedules was talazoparib 250mcg daily. The main toxicity was myelosuppression including grade 3/4 hematologic treatment-related adverse events (TRAEs). Dose modification occurred in 87% and 100% of patients for schedules A and B, respectively. Discontinuation due to TRAEs was 13% in schedule A and 10% in B. Ten out of 22 evaluable patients in schedule A and 5/16 patients in schedule B had a complete or partial response. Twelve out of 43 patients received ≥6 cycles of talazoparib after induction, with a 13-month median duration of maintenance.
Conclusion: We have established the recommended phase II dose of Talazoparib at 250mcg on a 3- or 7-day schedule with carboplatin AUC6 and paclitaxel 80 mg/m 2 on days 1, 8, 15 of 21-day cycles. This regimen is associated with significant myelosuppression, and in addition to maximizing supportive care, modification of the chemotherapy component would be a consideration for further development of this combination with the schedules investigated in this study.
(© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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